GENECARD-Gene Identification in Early-Onset CAD

描述(申请人提供)：在美国，冠状动脉疾病是导致死亡的唯一主要原因。冠状动脉疾病(CAD)也是导致残疾的主要原因。识别增加冠心病易感性的基因将对公众健康产生深远的影响，从增强易感个体改变行为和生活方式的动机到提供有关冠心病的发展和治疗的基本生物学和临床信息。冠心病是一种复杂的疾病，具有明确的遗传和环境风险因素。早发(早发)冠状动脉疾病(EOCAD)，定义为发病年龄小于50岁，已知具有特别强的遗传成分。然而，导致这种风险增加和对CAD的基本了解的实际基因仍然不清楚。我们的目标是在核心家庭的大样本中识别增加早发性冠心病易感性的基因，这些核心家庭至少有两名成员患有EOCAD，这是基于男性50岁或女性55岁之前的心肌梗死、外科手术或功能测试而确定的。我们已经完成了EOCAD的基因组筛选，使用了GENECARD研究收集的438个家庭的395个微卫星标记，这是一项涉及6个临床研究站点、葛兰素史克和杜克人类遗传学中心的合作研究。我们已经确定了9个区域，为这些家庭中的连锁提供了一致的证据。我们将集中在包含染色体3Q13-Q22的区域，为连锁提供强有力和一致的证据(MLS=2.3)。我们建议在最初的一组家系和另外一组近400个家系中对这些区域的微卫星标记进行后续基因分型。这些区域的候选基因以及在其他项目中进行的表达分析中确定的基因将使用连锁和基于家庭的关联进行分析。我们在为后续研究确定新的标记、SNPs和候选基因方面的努力将得到生物信息学分析和工具的帮助。我们坚信，对遗传因素和基因-环境相互作用的详细研究是确定有针对性的预防策略和更有效的治疗的关键步骤。

DESCRIPTION (provided by applicant): Coronary artery disease is the single leading cause of death in the US. Coronary Artery disease (CAD) is also a leading cause of disability. Identification of genes increasing susceptibility to CAD would have far reaching public health impact from enhancing motivation to make behavioral and lifestyle changes in susceptible individuals to providing basic biological and clinical information about the development and treatment of CAD. CAD is a complex disease with clear genetic and environmental risk factors. Early onset (premature) coronary artery disease (EOCAD), defined as age of onset less than 50 years of age, is known to have a particularly strong genetic component. However the actual genes leading to this increased risk and to a basic understanding of CAD remain obscure. Our goal is to identify genes increasing susceptibility to early onset coronary disease in a large sample of nuclear families with at least two members with EOCAD defined on the basis of a myocardial infarction, surgical procedure, or functional test before the age of 50 in men or 55 in women. We have completed a genome screen for EOCAD using 395 microsatellite markers in 438 families collected by the GENECARD study, a collaborative study involving 6 clinical investigative sites, GlaxoSmithKline and the Duke Center for Human Genetics. We have identified 9 regions providing consistent evidence for linkage in these families. We will concentrate on a region encompassing chromosome 3q13-q22 providing strong and consistent evidence for linkage (MLS=2.3). We propose to perform follow-up genotyping of microsatellite markers in these regions in the original set of families and in an additional set of almost 400 families. Candidate genes in those regions as well as genes identified from expression analyses carried out in other projects will be analyzed using linkage and family-based association. Our efforts in identifying new markers, SNPs and candidate genes for the follow-up studies will be aided by bioinformatics analyses and tools. We strongly believe that a detailed study of genetic factors and gene-environment interactions is an essential step to identifying targeted preventive strategies and more effective treatments.